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2017 European LeukemiaNet risk stratification of acute myeloid leukemia by genetics

2017 European LeukemiaNet risk stratification of acute myeloid leukemia by genetics
Risk category* Genetic abnormality
Favorable t(8;21)(q22;q22.1); RUNX1-RUNX1T1
inv(16)(p13.1;q22) or t(16;16)(p13.1;q22); CBFB-MYH11
Mutated NPM1 without FLT3-ITD or with FLT3-ITDlow
Biallelic mutated CEBPA
Intermediate Mutated NPM1 and FLT3-ITDhigh
Wild type NPM1 without FLT3-ITD or with FLT3-ITDlow (without adverse-risk genetic lesions)
t(9;11)(p21.3;q23.3); MLLT3-KMT2AΔ
Cytogenetic abnormalities not classified as favorable or adverse
Adverse t(6;9)(p23;q34.1); DEK-NUP214
t(v;11q23.3); KMT2A rearranged
t(9;22)(q34.1;q11.2); BCR-ABL1
inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2,MECOM(EVI1) –5 or del(5q); –7; –17/abn(17p)
Complex karyotype,◊ monosomal karyotype§
Wild type NPM1 and FLT3-ITDhigh
Mutated RUNX1¥
Mutated ASXL1¥
Mutated TP53‡
This table describes the European LeukemiaNet stratification of acute myeloid leukemia (AML) based on cytogenetic and molecular characteristics. Note the use of "allelic ratio" to stratify based on the FLT3-ITD mutation. Various research groups calculate this ratio differently and/or use other cutoff values.
* Prognostic impact of a marker is treatment-dependent and may change with new therapies.
¶ Low, low allelic ratio (<0.5); high, high allelic ratio (>0.5); semi-quantitative assessment of FLT3-ITD allelic ratio (using DNA fragment analysis) is determined as ratio of the area under the curve (AUC) "FLT3-ITD" divided by AUC "FLT3-wild type"; recent studies indicate that acute myeloid leukemia with NPM1 mutation and FLT3-ITD low allelic ratio may also have a more favorable prognosis and patients should not routinely be assigned to allogeneic hematopoietic-cell transplantation.[1-4]
Δ The presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent adverse-risk gene mutations.
◊ Three or more unrelated chromosome abnormalities in the absence of one of the World Health Organization-designated recurring translocations or inversions, ie, t(8;21), inv(16) or t(16;16), t(9;11), t(v;11)(v;q23.3), t(6;9), inv(3) or t(3;3); AML with BCR-ABL1.
§ Defined by the presence of one single monosomy (excluding loss of X or Y) in association with at least one additional monosomy or structural chromosome abnormality (excluding core-binding factor AML).[5]
¥ These markers should not be used as an adverse prognostic marker if they co-occur with favorable-risk AML subtypes.
‡ TP53 mutations are significantly associated with AML with complex and monosomal karyotype.[6-10]
References:
  1. Gale RE, Green C, Allen C, et al; Medical Research Council Adult Leukaemia Working Party. The impact of FLT3 internal tandem duplication mutant level, number, size, and interaction with NPM1 mutations in a large cohort of young adult patients with acute myeloid leukemia. Blood 2008; 111:2776.
  2. Pratcorona M, Brunet S, Nomdedéu J, et al. Favorable outcome of patients with acute myeloid leukemia harboring a low-allelic burden FLT3-ITD mutation and concomitant NPM1 mutation: relevance to postremission therapy. Blood 2013; 121:2734.
  3. Schlenk RF, Kayser S, Bullinger L, et al. Differential impact of allelic ratio and insertion site in FLT3-ITDpositive AML with respect to allogeneic transplantation. Blood 2014; 124:3441.
  4. Ho AD, Schetelig J, Bochtler T, et al. Allogeneic stem cell transplantation improves survival in patients with acute myeloid leukemia characterized by a high allelic ratio of mutant FLT3-ITD. Biol Blood Marrow Transplant 2016; 22:462.
  5. Breems DA, van Putten WLJ, De Greef GE, et al. Monosomal karyotype in acute myeloid leukemia: a better indicator of poor prognosis than a complex karyotype. J Clin Oncol 2008; 26:4791.
  6. Papaemmanuil E, Gerstung M, Bullinger L, et al. Genomic classification and prognosis in acute myeloid leukemia. N Engl J Med 2016;374:2209.
  7. Haferlach C, Dicker F, Herholz H, Schnittger S, Kern W, Haferlach T. Mutations of the TP53 gene in acute myeloid leukemia are strongly associated with a complex aberrant karyotype. Leukemia 2008; 22:1539.
  8. Bowen D, Groves MJ, Burnett AK, et al. TP53 gene mutation is frequent in patients with acute myeloid leukemia and complex karyotype, and is associated with very poor prognosis. Leukemia 2009; 23:203.
  9. Rücker FG, Schlenk RF, Bullinger L, et al. TP53 alterations in acute myeloid leukemia with complex karyotype correlate with specific copy number alterations, monosomal karyotype, and dismal outcome. Blood 2012; 119:2114.
  10. Devillier R. Mansat-De Mas V, Gelsi-Boyet V, et al. Role of ASXL1 and TP53 mutations in the molecular classification and prognosis of acute myeloid leukemias with myelodysplasia-related changes. Oncotarget 2015; 6:8388.
Reproduced with permission of the American Society of Hematology, from: Döhner H, Estey E, Grimwade D, et al. Diagnosis and Management of AML in Adults: 2017 ELN Recommendations from an International Expert Panel. Blood 2016; permission conveyed through Copyright Clearance Center, Inc. Copyright © 2016.
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